The FGF family of signaling molecules plays a central role in the regulation of many aspects of vertebrate embryogenesis, and is also important in the control of physiological and pathological processes in the adult. There is substantial evidence from previous genetic studies that one member of the FGF family, FGF8, is essential at multiple stages of embryogenesis. This proposal is focused on three key developmental processes that are dependent on FGF8 signaling: left-right axis- determination, limb development, and kidney development. The experiments proposed are aimed at using a genetic approach to elucidate the function of FgJ8 and other FGF family members in these processes. They take advantage of recent advances in methods for analyzing gene function in mice, including conditional loss- and gain-of-function in specific tissues, and reporter alleles for gene expression and protein distribution.
Each Specific Aim i ncludes the development of new lines of transgenic mice that will not only make it possible to answer specific questions and test hypotheses about these particular processes, but will also be extremely useful as tools for studies of many other aspects of vertebrate development in laboratories throughout the scientific community. The results of these studies should provide a deeper understanding of the mechanisms involved in establishing the basic body plan and the formation of limbs and kidneys. The information obtained will be relevant to understanding the mechanism of human development and the etiology of human birth defects, chronic diseases, and various forms of adult disease that originate during gestation.
